ABSTRACT Hypertension is a risk factor for cardiovascular and chronic kidney diseases, as well as cerebrovascular dysfunction and cognitive decline. Significantly, there are established sex differences in the development of hypertension. Overcoming the insufficiency of blood pressure control and treatment resistance commonly seen with current hypertension therapies will depend on understanding the systems, including within the brain, that are responsible for elevated blood pressure in males and females. Provocative recent evidence points to a critical role for brain inflammatory factors in the emergence of hypertension. Tumor necrosis factor alpha (TNF?) is a cytokine originally characterized as a macrophage-derived signaling molecule involved in systemic inflammation that is now known to be synthesized and released during normal, plastic, and pathological neural function by resident brain cells. TNF? is also known to modulate hypothalamic networks that coordinate sympathetic and neuroendocrine activity with blood pressure. TNF? signals via type 1 and type 2 receptors (TNFR1 and TNFR2, respectively). TNFR1 receptors are the major TNF? receptor in the brain with a high expression in the hypothalamic paraventricular nucleus (PVN). Within the brain, there is evidence that TNFR1 has key interactions with glutamate, an important substrate for neural signaling and plasticity implicated in autonomic regulation and blood pressure control. Significantly, estrogen signaling at estrogen receptor (ER), the major estrogen receptor in the PVN, is involved in hypothalamic glutamate plasticity associated with hypertension. However, the relationship between TNFR1, ER, and glutamate plasticity, during hypertension has never been established in males and females. This project will test the novel hypothesis that TNFR1 signaling in PVN neurons contributes to the glutamate receptor plasticity associated with slow-pressor AngII administration in a sex-dependent manner. A multidisciplinary strategy combining the use of genetic/molecular, biochemical, neurophysiological, and high-resolution neuroanatomical approaches will be used to investigate the role of TNFR1 signaling in glutamate receptor plasticity in the PVN. Mice will be made hypertensive by a form of angiotensin II-dependent slow onset-hypertension with clinical relevance. The following Specific Aims will be addressed: Aim 1. TNFR1 in the PVN plays differing roles in the development of the slow-pressor response to AngII in male and female mice. Aim 2. TNFR1 differentially modulates PVN glutamate receptor signaling in male and female mice. Aim 3. ER contributes to sex-differences in TNFR1- glutamate signaling during hypertension. This project has the potential to expand our understanding of neural-inflammatory signaling and gender differences in hypertension and offer novel insights into the neural regulation of blood pressure control.